people suffer from Parkinson's disease, a disorder of
the nervous system that affects movement and worsens
over time. As the world's population ages, it's
estimated that the number of people with the disease
will rise sharply. Yet despite several effective
therapies that treat Parkinson's symptoms, nothing slows
While it's not known what exactly
causes the disease, evidence points to one particular
culprit: a protein called α-synuclein. The protein,
which has been found to be common to all patients with
Parkinson's, is thought to be a pathway to the disease
when it binds together in "clumps," or aggregates, and
becomes toxic, killing the brain's neurons.
at UCLA have found a way to prevent these clumps from
forming, prevent their toxicity and even break up
UCLA professor of neurology Jeff
Bronstein and UCLA associate professor of neurology Gal
Bitan, along with their colleagues, report the
development of a novel compound known as a "molecular
tweezer," which in a living animal model blocked
α-synuclein aggregates from forming, stopped the
aggregates' toxicity and, further, reversed aggregates
in the brain that had already formed. And the tweezers
accomplished this without interfering with normal brain
The research appears in the current
online edition of the journal Neurotherapeutics.
There are currently more than 30
diseases with no cure that are caused by protein
aggregation and the resulting toxicity to the brain or
other organs, including Parkinson's, Alzheimer's and
Type 2 diabetes. It is therefore critical, Bronstein
said, to find a way to stop this aggregation process.
Over the last two decades, researchers and
pharmaceutical companies have attempted to develop drugs
that would prevent abnormal protein aggregation, but so
far, they have had little or no success.
aggregates are a natural target for a drug, finding a
therapy that targets only the aggregates is a
complicated process, Bronstein said. In Parkinson's, for
example, the protein implicated in the disorder,
α-synuclein, is naturally ubiquitous throughout the
"Its normal function is not well
understood, but it may play a role in aiding
communication between neurons," Bronstein said. "The
trick, then, is to prevent the α-synuclein protein
aggregates and their toxicity without destroying
α-synuclein's normal function, along with, of course,
other healthy areas of the brain.
Bronstein collaborated with Bitan,
who had been working with a particular molecular tweezer
he had developed called CLR01. Molecular tweezers are
complex molecular compounds that are capable of binding
to other proteins. Shaped like the letter "C," these
compounds wrap around chains of lysine, a basic amino
acid that is a constituent of most proteins.
in cell cultures, the researchers found that CLR01 was
able to prevent α-synuclein from forming aggregates,
prevent toxicity and even break up existing aggregates.
surprising aspect of the work," Bronstein said, "is that
despite the ability of the compound to bind to many
proteins, it did not show toxicity or side effects to
normal, functioning brain cells."
"We call this
unique mechanism 'process-specific,' rather than the
common protein-specific inhibition," Bitan added,
meaning the compound only attacked the targeted
aggregates and nothing else.
The researchers next tried their
tweezers in a living animal, the zebrafish, a tropical
freshwater fish commonly found in aquariums. The
zebrafish is a popular animal for research because it is
easily manipulated genetically, develops rapidly and is
transparent, making the measurement of biological
Using a transgenic zebrafish model
for Parkinson's disease, the researchers added CLR01 and
used fluorescent proteins to track the tweezer's effect
on the aggregations. They found that, just as in cell
cultures, CLR01 prevented α-synuclein aggregation and
neuronal death, thus stopping the progression of the
disorder in the living animal model.
Being able to
prevent α-synuclein from aggregating, prevent toxicity
and break up existing aggregates is a very encouraging
result, but still, at the end of the day, "we've only
stopped Parkinson's in zebrafish," Bronstein said.
he said, "all of these benefits of CLR01 were found
without any evidence of toxicity. And taken together,
CLR01 holds great promise as a new drug that can slow or
stop the progression of Parkinson's and related
disorders. This takes us one step closer to a cure."
are already studying CLR01 in a mouse model of
Parkinson's and say they hope this will lead to human
Other authors of the study included
Shubhangi Prabhudesai, Sharmistha Sinha, Aida Attar,
Aswani Kotagiri, Arthur G. Fitzmaurice, Ravi Lakshmanan,
Magdalena I. Ivanova, Joseph A. Loo and Mark Stahl, all
of UCLA, and Frank-Gerrit Klärner and Thomas Schrader of
the University of Duisburg–Essen in Germany.
provided by multiple sources, including the Levine
Foundation, the American Health Assistance Foundation,
the UCLA Jim Easton Consortium for Alzheimer's Drug
Discovery and Biomarker Development, the Team
Parkinson/Parkinson Alliance, and the National
Institutes of Health. Full conflict-of-interest
disclosure is available in the electronic supplementary
material for this article online.
Department of Neurology, with over 100 faculty
members, encompasses more than 20 disease-related
research programs, along with large clinical and
teaching programs. These programs cover brain mapping
and neuroimaging, movement disorders, Alzheimer's
disease, multiple sclerosis, neurogenetics, nerve and
muscle disorders, epilepsy, neuro-oncology, neurotology,
neuropsychology, headaches and migraines,
neurorehabilitation, and neurovascular disorders. The
department ranks in the top two among its peers
nationwide in National Institutes of Health funding.
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